title: Pneumococcal IgA1 protease subverts specific protection by human IgA1.
abstract: Bacterial immunoglobulin A1 (IgA1) proteases may sabotage the protective effects of IgA. In vitro, both exogenous and endogenously produced IgA1 protease inhibited phagocytic killing of Streptococcus pneumoniae by capsule-specific IgA1 human monoclonal antibodies (hMAbs) but not IgA2. These IgA1 proteases cleaved and reduced binding of the the effector Fcα1 heavy chain but not the antigen-binding F(ab)/light chain to pneumococcal surfaces. In vivo, IgA1 protease-resistant IgA2, but not IgA1 protease-sensitive IgA1, supported 60% survival in mice infected with wild-type S. pneumoniae. IgA1 hMAbs protected mice against IgA1 protease-deficient but not -producing pneumococci. Parallel mouse sera with human IgA2 showed more efficient complement-mediated reductions in pneumococci with neutrophils than did IgA1, particularly with protease-producing organisms. After natural human pneumococcal bacteremia, purified serum IgG inhibited IgA1 protease activity in 7 of 11 patients (64%). These observations provide the first evidence in vivo that IgA1 protease can circumvent killing of S. pneumoniae by human IgA. Acquisition of IgA1 protease-neutralizing IgG after infection directs attention to IgA1 protease both as a determinant of successful colonization and infection and as a potential vaccine candidate.
authors.affiliation: Mucosal and Vaccine Research Colorado (MAVRC), Division of Infectious Diseases, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: E N
authors.initials: EN
authors.lastname: Janoff
authors.affiliation: Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Rubins
authors.affiliation: Veterans Affairs Medical Center, Denver Veterans Affairs Medical Center, Denver, Colorado, USA.
authors.forename: C
authors.initials: C
authors.lastname: Fasching
authors.affiliation: Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA.
authors.forename: D
authors.initials: D
authors.lastname: Charboneau
authors.affiliation: Mucosal and Vaccine Research Colorado (MAVRC), Division of Infectious Diseases, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Rahkola
authors.affiliation: Department of Medicine and Division of Gastroenterology, Tufts-New England Medical Center, Boston, Massachusetts, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Plaut
authors.affiliation: Departments of Microbiology and Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Weiser
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D051379:Mice; D010587:Phagocytosis / Q000276:immunology; D011008:Pneumococcal Infections / Q000276:immunology* / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000201:enzymology* / Q000276:immunology*
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D012697:Serine Endopeptidases; C021433:IgA-specific serine endopeptidase